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Different topoisomerase II antitumor drugs direct similar specific long-range fragmentation of an amplified c-MYC gene locus in living cells and in high-salt-extracted nuclei.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 1995 Jan 03; Vol. 92 (1), pp. 102-6. - Publication Year :
- 1995
-
Abstract
- We have analyzed the long-range distribution of topoisomerase II-mediated cleavages induced in an amplified human c-MYC gene locus in the presence of several antitumor agents. The long-range cleavage patterns were found to be nonrandom and similar for all antitumor drugs tested. Cleavages occurred within several kilobase-long areas (approximately 5 kb) highly accessible to topoisomerase II and separated by extended regions (approximately 70-100 kb) of less accessibility, possibly reflecting the mode of DNA organization into loops along the chromosome. Within the cleavage areas, the patterns of cleavage sites showed a certain dependence on the type of drug used for entrapment of topoisomerase II-DNA complexes. Importantly, distribution of cleavage areas in native chromatin and histone-depleted nuclei was very similar, if not identical, suggesting that the primary target of antitumor agents in vivo is topoisomerase II associated with the high-salt-insoluble nuclear matrix. These data show that matrix-attached DNA is preferentially damaged by topoisomerase II-targeting agents, which may be an important cellular event contributing to drug-induced cell death.
- Subjects :
- Amsacrine pharmacology
Carcinoma, Small Cell
Cell Fractionation methods
Cell Line
Cell Nucleus metabolism
Cell Nucleus ultrastructure
DNA, Neoplasm metabolism
Etoposide pharmacology
Exons
Humans
Lung Neoplasms
Restriction Mapping
Saline Solution, Hypertonic
Teniposide pharmacology
Topoisomerase II Inhibitors
Tumor Cells, Cultured
Antineoplastic Agents pharmacology
Cell Nucleus drug effects
DNA Damage
DNA Topoisomerases, Type II metabolism
Genes, myc
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 92
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 7816796
- Full Text :
- https://doi.org/10.1073/pnas.92.1.102